Anxious responses to predictable and unpredictable aversive events

Anxiety induced by 2 types of predictable and unpredictable aversive stimuli, an unpleasant shock or a less aversive airblast to the larynx, were investigated in a between-group design. Participants anticipated predictable (signaled) or unpredictable (not signaled) aversive events, or no aversive event. Unpredictable, relative to predictable, contexts potentiated the startle reflex in the shock group but not in the airblast group. These data suggest that unpredictability can lead to a sustained level of anxiety only when the pending stimulus is sufficiently aversive. Because predictable and unpredictable danger may induce different types of aversive responses, the proposed design can serve as a useful tool for studying the neurobiology and psychopharmacology of fear and anxiety.     

Contextual fear induced by unpredictability in a human fear conditioning preparation is related to the chronic expectation of a threatening US

The present study was set up to investigate cued and contextual fear in situations of (un)predictability in a human fear conditioning paradigm. Forty-nine participants were presented with two different contexts (switching on and off the central lighting of the experimental room). In the predictable context, a visual cue (CS1) was systematically followed by an electrocutaneous stimulus (US). In the unpredictable context, CS2 was presented explicitly unpaired with the US. Dependent variables were online US-expectancy ratings and fear-potentiated startle. First, in both measures, the results showed significantly more fear elicited by CS1 than by CS2. Second, larger startle amplitudes during the intertrial intervals demonstrated more contextual fear in the unpredictable than in the predictable context. Hence, these findings illustrate that unpredictability increases contextual fear. Moreover, the US-expectancy ratings during the intertrial intervals were also higher in the unpredictable than in the predictable context. This last finding suggests that a chronic expectation of the threatening US is responsible for sustained levels of anxiety in unpredictable situations.     

Temporal-difference prediction errors and Pavlovian fear conditioning: role of NMDA and opioid receptors

Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear conditioning. In Stage I, rats received conditioned stimulus A (CSA) paired with shock. In Stage II, they received pairings of CSA and CSB with shock that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB --> CSA, was followed by shock. The change in intratrial durations supported fear learning to CSB but reduced fear of CSA, revealing the operation of TD prediction errors. N-methyl- D-aspartate (NMDA) receptor antagonism prior to Stage III prevented learning, whereas opioid receptor antagonism selectively affected predictive learning. These findings support a role for TD prediction errors in fear conditioning. They suggest that NMDA receptors contribute to fear learning by acting on the product of predictive error, whereas opioid receptors contribute to predictive error.     

Enhanced discrimination between threatening and safe contexts in high-anxious individuals

Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality. Two virtual office rooms served as the conditioned contexts. One virtual office room (CXT+) was paired with unpredictable electrical stimuli. In the other virtual office room, no electrical stimuli were delivered (CXT−). High-anxious participants tended to show faster acquisition of startle potentiation in the CXT+ versus the CXT− than low-anxious participants. This enhanced contextual fear learning might function as a risk factor for anxiety disorders that are characterized by sustained anxiety.     

Prior chronic nicotine impairs cued fear extinction but enhances contextual fear conditioning in rats

Clinical observations have shown a link for the high comorbid rate between smoking and psychiatric disorders, including anxiety disorders. However, little is known about the neural mechanism underlying the progression from nicotine dependence to an anxiety disorder. A deficit in fear extinction in general is considered to contribute to anxiety disorders. The aim of the present study is to investigate the effects of chronic nicotine on fear extinction in rats. Rats were administrated s.c. nicotine twice per day for 14 days. Two weeks after the last injection rats received a cued or contextual fear conditioning session. Twenty-four hours and 48 h after conditioning, rats received an extinction training session and an extinction test session, respectively. Percent freezing was assessed during all phases of training. In the cued task, prior chronic nicotine did not affect the acquisition of fear response or the within-session fear extinction, but impaired the between-session fear extinction. In the contextual task, the same nicotine treatment schedule did not affect the acquisition of fear response or the within- and between-session fear extinction, but enhanced the retention of fear conditioning. This prior chronic nicotine-induced deficit in cued fear extinction and/or enhanced fear to context may be one of the critical components that contribute to the progression from nicotine dependence to an anxiety disorder.     

Evaluative conditioning affects the subsequent acquisition of differential fear conditioning as indexed by electrodermal responding and stimulus evaluations

It is currently unclear whether the acquisition of negative stimulus valence in evaluative and fear conditioning paradigms is interrelated or independent. The present study used a transfer paradigm to address this question. Three groups of participants were trained in a picture-picture evaluative conditioning paradigm before completing acquisition of differential fear conditioning using graphical shapes as conditional stimuli (CSs). In group congruent, the shape used as CS+ (paired with the US during fear conditioning) was paired with negative pictures, whereas the shape used as CS− (presented alone during fear conditioning) was paired with positive pictures. In group incongruent, the shape used as CS+ was paired with positive pictures, whereas the shape used as CS− was paired with negative pictures. In group different, different shapes were employed in evaluative and fear conditioning. Acquisition of differential electrodermal responses emerged within fewer acquisition trials in groups congruent and different than in group incongruent. Transfer of evaluative learning across paradigms was evident only after removal of participants who failed to display evaluative conditioning. The current research indicates that stimulus valence acquired during evaluative conditioning transfers to fear conditioning and will differentially affect the acquisition of fear learning as indexed by subjective evaluations and electrodermal responses. The findings suggest that evaluative and fear conditioning are not independent.     

Differences between trait fear and trait anxiety: Implications for psychopathology

Fear and anxiety are poorly delineated in much of the clinical and research literatures. Although some theorists and researchers have posited explanations for how trait fear and trait anxiety differ, many others conceptualize the constructs as largely or entirely interchangeable. The primary goals of this review are to examine clinical conceptualizations and neurobiological studies of fear and anxiety, examine the animal and human literatures on the correlates of fear and anxiety, provide clearer definitions of these two constructs, and discuss their implications for psychopathology. A secondary goal is to evaluate content of self-report measures of trait fear and anxiety, and meta-analyze the relations between self-reported trait fear and anxiety. We found that existing measures share significant content overlap across constructs. Despite this overlap, our meta-analysis revealed only a moderate (r = 0.32) relationship between measures of trait fear and anxiety, with an even lower relationship (r = 0.14) when we examined trait fear measures operationalized in terms of harm avoidance. These findings suggest that fear and anxiety are largely distinct emotions, and that psychological disorders of trait fear and trait anxiety warrant classification in separate higher-order categories. Moreover, they suggest that future research should focus on deriving more content valid measures of trait fear and trait anxiety from the neurobiological and diagnostic literatures.     

Effects of cued and contextual fear on sleep in DBA/2J mice

Fear conditioning alters sleep, with the most consistent effect being significant reductions in rapid eye movement sleep (REM). DBA/2 (D2) mice show behavioral signs of anxiety, respond greater to shock training, and potentially behave differently in cued and contextual fear, raising the question of how fear conditioning would affect their sleep. D2 mice were implanted to record sleep via telemetry. After baseline sleep recording, groups of D2 mice were trained in cued (15 tone–shock pairings) and contextual (15 non-cued shocks) fear on 4 consecutive days. Cue and context control mice were given identical training but were never presented with shock. Sleep was recorded after shock training and after presentation of cue or context alone. Shock training produced selective suppression of REM. On the day after shock training was completed, light period sleep was significantly altered in mice in the cued fear group, but not in the contextual fear group. Subsequent presentation of fearful cues and re-exposure to the fearful contexts also produced significant reductions in REM. The effects of fear conditioning on sleep in D2 mice and other mouse strains and the differential effects of cued and contextual fear on sleep are discussed.     

Competition between an avoidance response and a safety signal: Evidence for a single learning system

Two experiments examined competition between an instrumental avoidance response and a Pavlovian safety signal for association with omission of electric shock in a human fear conditioning paradigm. Self-reported shock expectancies and skin conductance responses were consistent with blocking of learning of the instrumental contingency by prior training of the Pavlovian contingency, and vice versa. The results support the idea that a common learning mechanism underlies both Pavlovian and instrumental conditioning. The expectancy data suggest that this learning mechanism is cognitive in nature, and that Pavlovian and instrumental learning involve external and internal attributions, respectively. The procedure may thus serve as a laboratory model for attributional processes involved in the acquisition of threat expectancies in anxiety and anxiety disorders.     

Relations between anxiety disorders and fear of childbirth during late pregnancy

In a group of late pregnant women we investigated the prevalence of extreme fear of childbirth and anxiety disorders, both assessed by means of diagnostic interviews. We also explored the relation between anxiety disorders and extreme fear of childbirth on the one hand and fear of childbirth, as measured by means of the Wijma Delivery Expectancy/Experience Questionnaire (W‐DEQ), on the other hand. A subgroup of women (2.4%) fulfilled the criteria for a phobia‐like fear of childbirth. Anxiety disorders were related to fear of childbirth, as measured by the W‐DEQ. The group of women with extreme fear of childbirth (with or without anxiety disorders) had obviously the highest W‐DEQ scores. But also in the group of women with anxiety disorders only the W‐DEQ scores were high. Clinical assessment of anxiety disorders among pregnant women should be considered, above all in women who report fear of the anticipated delivery. Copyright © 2002 John Wiley & Sons, Ltd.     

Role of conceptual knowledge in learning and retention of conditioned fear

Associating sensory cues with aversive outcomes is a relatively basic process shared across species. Yet higher-order cognitive processes likely contribute to associative fear learning in many circumstances, especially in humans. Here we ask whether fears can be acquired based on conceptual knowledge of object categories, and whether such concept-based fear conditioning leads to enhanced memory representations for conditioned objects. Participants were presented with a heterogeneous collection of images of animals and tools. Objects from one category were reinforced by an electrical shock, whereas the other category was never reinforced. Results confirmed concept-based fear learning through subjective report of shock expectancy, heightened skin conductance responses, and enhanced 24 h recognition memory for items from the conditioned category. These results provide novel evidence that conditioned fear can generalize through knowledge of object concepts, and sheds light on the persistent nature of fear memories and category-based fear responses symptomatic of some anxiety disorders.     

Chemical lesion of the bed nucleus of the stria terminalis blocks the behavioral consequences of uncontrollable stress

Uncontrollable or inescapable shock (IS) produces behavioral changes that are characterized by a sensitized fear system and a deficit in fight-flight responding. These behavioral changes have been argued to represent an anxiety-like state produced by the uncontrollability of the stressor. The bed nucleus of the stria terminalis (BNST) has been implicated in the mediation of long-duration responses to unpredictable stressors, which have also been argued to represent anxiety. In the present study, the effects of BNST chemical lesion on the IS-induced sensitization of freezing to an environment previously paired with shock and the IS-induced impairment of escape responding were investigated. BNST chemical lesion blocked the potentiation of freezing and the increases in escape latency that normally follow IS.     

Effects of exercise on Pavlovian fear conditioning

Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning.     

The influence of gonadal hormones on conditioned fear extinction in healthy humans

Recent rodent studies suggest that gonadal hormones influence extinction of conditioned fear. Here we investigated sex differences in, and the influence of estradiol and progesterone on, fear extinction in healthy humans. Men and women underwent a two-day paradigm in which fear conditioning and extinction learning took place on day 1 and extinction recall was tested on day 2. Visual cues were used as the conditioned stimuli and a mild electric shock was used as the unconditioned stimulus. Skin conductance was recorded throughout the experiment and used to measure conditioned responses (CRs). Blood samples were obtained from all women to measure estradiol and progesterone levels. We found that higher estradiol during extinction learning enhanced subsequent extinction recall but had no effects on fear acquisition or extinction learning itself. Sex differences were only observed during acquisition, with men exhibiting significantly higher CRs. After dividing women into low- and high-estradiol groups, men showed comparable extinction recall to high-estradiol women, and both of these groups showed higher extinction recall than low-estradiol women. Therefore, sex differences in extinction memory emerged only after taking into account women's estradiol levels. Lower estradiol may impair extinction consolidation in women. These findings could have practical applications in the treatment of anxiety disorders through cognitive and behavioral therapies.     

Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults

Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 58: 471–481, 2016.     

Contextual fear-potentiated startle conditioning in humans: replication and extension

Contextual fear conditioning was examined using the startle reflex in two groups of participants over two sessions separated by 1/2 h. The conditioned stimulus (CS) was paired (paired group) or not (unpaired group) with an unpleasant shock during conditioning. The paired group showed conditioning to the CS that was well retained over the retention interval. Session I intertrial interval startles--a measure of contextual conditioning--were greater in the unpaired compared to the paired group. Context conditioning was retained in Session 2 and was present before the shock electrodes were attached. Self-rating of state anxiety, arousal, and pleasure indicated differential changes in mood from Session 1 to Session 2 in the two groups, with the unpaired group showing relatively greater negative affects compared to the paired group. These results indicate that unpredictable shocks lead to greater context conditioning as measured by startle and self-reports.     

Enhanced fear recall and emotional arousal in rats recovering from chronic variable stress

Emergence of posttraumatic-like behaviors following chronic trauma is of interest given the rising prevalence of combat-related posttraumatic stress disorder (PTSD). Stress associated with combat usually involves chronic traumatization, composed of multiple, single episode events occurring in an unpredictable fashion. In this study, we investigated whether rats recovering from repeated trauma in the form of chronic variable stress (CVS) express posttraumatic stress-like behaviors and dysregulated neuroendocrine responses. Cohorts of Long-Evans rats underwent a 7 day CVS paradigm followed by behavioral and neuroendocrine testing during early (16 h post CVS) and delayed (7 day) recovery time points. A fear conditioning-extinction-reminder shock paradigm revealed that CVS induces exaggerated fear recall to reminder shock, suggestive of potentiated fear memory. Rats with CVS experience also expressed a delayed expression of fearful arousal under aversive context, however, social anxiety was not affected during post-CVS recovery. Persistent sensitization of the hypothalamic-pituitary-adrenocorticotropic response to a novel acute stressor was observed in CVS exposed rats. Collectively, our data are consistent with the constellation of symptoms associated with posttraumatic stress syndrome, such as re-experiencing, and arousal to fearful contexts. The CVS-recovery paradigm may be useful to simulate trauma outcomes following chronic traumatization that is often associated with repeated combat stress.     

Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear

Fear conditioning and fear extinction play key roles in the development and treatment of anxiety-related disorders, yet there is little information concerning experiential variables that modulate these processes. Here we examined the impact of exposure to a stressor in a different environment on subsequent fear conditioning and extinction, and whether the degree of behavioral control that the subject has over the stressor is of importance. Rats received a session of either escapable (controllable) tail shock (ES), yoked inescapable (uncontrollable) tail shock (IS), or control treatment (home cage, HC) 7 days before fear conditioning in which a tone and foot shock were paired. Conditioning was measured 24 h later. In a second experiment rats received ES, IS or HC 24 h after contextual fear conditioning. Extinction then occurred every day beginning 7 days later until a criterion was reached. Spontaneous recovery of fear was assessed 14 days after extinction. IS potentiated fear conditioning when given before fear conditioning, and potentiated fear responding during extinction when given after conditioning. Importantly, ES potently interfered with later fear conditioning, decreased fear responding during fear extinction, and prevented spontaneous recovery of fear. Additionally, we examined if the activation of the ventral medial prefrontal cortex (mPFCv) by ES is critical for the protective effects of ES on later fear conditioning. Inactivation of the mPFCv with muscimol at the time of the initial experience with control prevented ES-induced reductions in later contextual and auditory fear conditioning. Finally, we explored if the protective effects of ES extended to an unconditioned fear stimulus, ferret odor. Unlike conditioned fear, prior ES increased the fear response to ferret odor to the same degree as did IS.     

Hemispheric differences in protein kinase C betaII levels in the rat amygdala: baseline asymmetry and lateralized changes associated with cue and context in a classical fear conditioning paradigm

The amygdala is critically important for fear learning, and specific kinases have been implicated as contributors to the mechanisms that underlie learning. We examined levels of protein kinase C betaII (PKC betaII) in the left and right lateral and basolateral nuclei (LA/BLA) of the amygdala from animals that were classically fear conditioned with tones as cues and footshocks. Groups consisted of animals that received neither tones nor shocks, paired tones and shocks, or unpaired tones and shocks. At 1 h after conditioning, some animals from each group were used for biochemical measurements of PKC betaII levels and other animals were given probe trials to assess freezing behavior to cue and context. The levels of PKC betaII were greater in the left hemisphere in animals receiving neither tones nor shocks and animals receiving paired tones and shocks. PKC betaII levels were greater in the right hemisphere of animals receiving randomly presented tones and shocks. Freezing times to cue were long (>80% of probe trial time) in both the paired tone/shock and randomly unpaired tone/shock groups. Freezing times to context were long in the unpaired tone/shock group, but not the paired tone/shock group. Correlational analyses showed that freezing times to context, but not cue, precisely predicted the right/left relation of PKC betaII levels in the LA/BLA: the greater the time spent freezing to context, the greater the increase in right hemisphere PKC betaII levels. We conclude that fear conditioning causes hemisphere and input specific increases in PKC betaII in the rat LA/BLA.     

Selectivity of conditioned fear of touch is modulated by somatosensory precision

Learning to initiate defenses in response to specific signals of danger is adaptive. Some chronic pain conditions, however, are characterized by widespread anxiety, avoidance, and pain consistent with a loss of defensive response specificity. Response specificity depends on ability to discriminate between safe and threatening stimuli; therefore, specificity might depend on sensory precision. This would help explain the high prevalence of chronic pain in body areas of low tactile acuity, such as the lower back, and clarify why improving sensory precision may reduce chronic pain. We compared the acquisition and generalization of fear of pain‐associated vibrotactile stimuli delivered to either the hand (high tactile acuity) or the back (low tactile acuity). During acquisition, tactile stimulation at one location (CS+) predicted the noxious electrocutaneous stimulation (US), while tactile stimulation at another location (CS−) did not. Responses to three stimuli with decreasing spatial proximity to the CS+ (generalizing stimuli; GS1–3) were tested. Differential learning and generalization were compared between groups. The main outcome of fear‐potentiated startle responses showed differential learning only in the hand group. Self‐reported fear and expectancy confirmed differential learning and limited generalization in the hand group, and suggested undifferentiated fear and expectancy in the back group. Differences in generalization could not be inferred from the startle data. Specificity of fear responses appears to be affected by somatosensory precision. This has implications for our understanding of the role of sensory imprecision in the development of chronic pain.